The long term goal of the proposed research is to determine the role and mechanism of neurogenic inflammation in interstitial cystitis (IC). IC is a disease of the urinary bladder characterized by extreme frequency of urination, urgency, and pelvic pain. This disease occurs in the population at a frequency of 5.5/10,000 and is ten times more common in females than males. IC can be devastating. Chronic pain, coupled with the need to urinate frequently, affects patients' ability to maintain employment, marital relationships, and mental health. Treatment of this disease, when successful, appears to offer only temporary relief. The cause of IC is unknown. The observation of chronic pelvic pain and inflammation of the bladder without evidence of infection suggests that neurogenic inflammation may be a component of the disease and, possibly, the cause of this syndrome. Neurogenic inflammation and local immune responses are mediated by release of the neuropeptide substance P from peripheral neurons in skin, airways, joints and the intestine resulting in inflammatory diseases such as arthritis, asthma and inflammatory bowel disease. Although the urinary bladder is innervated by substance P- containing afferent neurons and urothelial cells are capable of immunologic activation, the role of neurogenic inflammation in interstitial cystitis has not been demonstrated. In this application we propose to demonstrate the induction of neurogenic inflammation in chemically-induced cystitis in the rat. This will demonstrate the capability of the mammalian bladder to mount a neuronally provoked local immune response and serve as an animal model for testing prevention and treatment strategies targeted at blocking neurogenic inflammation. In addition, we will determine whether molecular alterations typical of neurogenic inflammation have occurred in feline and human IC bladder.